肝癌，尤其是肝细胞癌（HCC），对全球人类生命构成了重要的威胁。为了推动创新诊断和治疗方法的发展，有必要研究HCC的隐藏特征，特别是其三维基因组结构，该结构目前尚不明确。本研究使用现场Hi-C和转座酶可接入染色质测序技术，研究了四株HCC细胞系（Hep3B，Huh1，Huh7和SNU449）的三维基因组组织。我们的发现显示，HCC细胞系与人类乳腺上皮细胞（HMECs）相比，具有更多的长程内/间染色体相互作用。令人意外的是，HCC细胞系在兆碱（Mb）尺度上显示了与细胞系特异性的区室修饰，这可能有助于确定HCC亚型。在子兆碱（sub-Mb）尺度上，我们观察到HCC细胞系内TAD（拓扑相关域）相互作用和染色质环的减少，与HMECs相比。最后，我们发现了SLC8A1的基因表达与其3D染色质架构之间的相关性；该基因编码一种钠钙抗转运蛋白，其调节已知能引起细胞凋亡。通过比较HCC细胞系和HMECs，我们的研究结果表明HCC细胞系具有独特的3D基因组组织，与正常细胞和其他癌细胞不同，基于区室、TAD和染色质环的分析。总体而言，我们将此作为证据支持基因组组织在癌症表型决定中起着关键作用。进一步探索HCC的表观遗传学将有助于更好地理解特定的基因调控机制，并发现癌症治疗的新靶点。

Liver cancer, particularly hepatocellular carcinoma (HCC), poses a significant global threat to human lives. To advance the development of innovative diagnostic and treatment approaches, it is essential to examine the hidden features of HCC, particularly its 3D genome architecture, which is not well understood. In this study, we investigated the 3D genome organization of four HCC cell lines-Hep3B, Huh1, Huh7, and SNU449-using in situ Hi-C and assay for transposase-accessible chromatin sequencing. Our findings revealed that HCC cell lines had more long-range interactions, both intra-and interchromosomal, compared to human mammary epithelial cells (HMECs). Unexpectedly, HCC cell lines displayed cell line-specific compartmental modifications at the megabase (Mb) scale, which could potentially be leveraged in determining HCC subtypes. At the sub-Mb scale, we observed decreases in intra-TAD (topologically associated domain) interactions and chromatin loops in HCC cell lines compared to HMECs. Lastly, we discovered a correlation between gene expression and the 3D chromatin architecture of SLC8A1, which encodes a sodium-calcium antiporter whose modulation is known to induce apoptosis by comparison between HCC cell lines and HMECs. Our findings suggest that HCC cell lines have a distinct 3D genome organization that is different from those of normal and other cancer cells based on the analysis of compartments, TADs, and chromatin loops. Overall, we take this as evidence that genome organization plays a crucial role in cancer phenotype determination. Further exploration of epigenetics in HCC will help us to better understand specific gene regulation mechanisms and uncover novel targets for cancer treatment.